Sensing Changes in Tissue Stiffness Central to Many Neurological Disorders

Dr. Byzova found that microglia sense and respond to changes in tissue stiffness, a hallmark of many neurological and retinal disorders, and identified a related signaling cascade that may be targeted to correct microglial response and potentially treat the associated disorders.

03/11/2020

Many neurological and retinal disorders—including Alzheimer’s disease, multiple sclerosis and macular degeneration—are characterized by changes in tissue stiffness of the brain and eye, which are normally very soft. Up until now, the mechanisms and consequences of these changes have not been well defined.

In a new study published in Nature Communications, Tatiana Byzova, PhD, Department of Neurosciences, and her team—including first author Tejasvi Dudiki, PhD, a research associate in her lab—showed that microglia (the brain’s immune cells) sense and respond to tissue stiffness, and that the proteins kindlin-3 and TGFβ1 (transforming growth factor beta 1) mediate this process.

Their findings suggest that adjusting microglial responses may be a viable therapeutic approach to help treat or prevent the many conditions associated with mechanical stiffness of the central nervous system (CNS), which range from scarring to neurodegeneration and even brain tumors.

Microglia are on constant patrol of the CNS, moving about the brain to survey tissues and respond if any abnormalities are detected. To understand microglia behavior, the researchers studied retinal models, as the retina exhibits a natural stiffness gradient.

They saw that in the stiffest tissues, as typically accompany brain injuries like lesions or tumors, the normal microglial response is to bipolarize. Using hydrogels (artificial tissue that mimics the mechanical properties of the brain), Dr. Byzova’s team observed that bipolarization results in a dramatic reduction in levels of TGFβ1—a protein secreted by microglia that is related to cell proliferation and extracellular matrix composition.

Kindlin-3, they found, is an important regulator of this response. The microglia did not respond to stiffness in kindlin-3’s absence, which resulted in vascular lesions similar to retinal angiomatous proliferation, a subset of age-related macular degeneration.

“Based on our findings, we believe that higher than normal levels of TGFβ1 result in overactive cell proliferation and extracellular matrix generation, which leads to unorganized vasculature,” said Dr. Byzova.

“Many neurological and neurodegenerative disorders also put patients at increased risk for similar vascular abnormalities. In the CNS, these vascular malformations may easily rupture, leading to brain injury and death.”  

The researchers went on to show that these vasculature abnormalities can be corrected by reintroducing kindlin-3 (or by inhibition of TGFβ1 signaling).

It is important to note that kindlin-3 is widely reported to be upregulated in a host of neurological disorders—including Alzheimer’s disease, Parkinson’s disease, schizophrenia, HIV-associated neurocognitive disorders and high-grade glioblastomas—and its complete absence is known to cause leukocyte adhesion deficiency (a severe and rare disorder previously discovered in the Byzova lab). As such, Dr. Byzova believes that preventing conditions triggered by mechanical stiffness of the CNS will require tight regulation of kindlin-3 and TGFβ1 expression in microglia, although additional research will be necessary.

The study was funded by the National Heart, Lung and Blood Institute (part of the National Institutes of Health). Dr. Byzova holds the Robert Canova Chair in Angiogenesis Research at Cleveland Clinic.

Image: Vascular lesions develop in response to kindlin-3 knockout



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